Coenzyme A-independent transacylase (CoA-IT) is an enzyme responsible for the movement of arachidonate between phospholipid molecular species of inflammatory cells. CoA-IT removes arachidonate from the sn-2 position of 1-acyl-containing phospholipids, such as 1-acyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-acyl-2-arachidonoyl-GPC). It then transfers that arachidonate to a suitable lyso-phospholipid acceptor, such as 1-alkyl-2-lyso-GPC and 1-alkenyl-2-lyso-sn-glycero-3-phospho-ethanolamine (Sugiura et al., J. Biol. Chem. 262: 1199-1205 (1987); Kramer and Deykin, Biol. Chem. 258: 13806-13811 (1983); Chilton et al., J. Biol. Chem. 258: 7268-7271 (1983)). This activity is selective for 20 carbon fatty acyl groups and is the mechanism by which inflammatory cells move arachidonate into specific phospholipid pools prior to its release (Winkler and Chilton, Drug News Perspec. 6: 133-138 (1993); Snyder et al., J. Lipid Mediat. 10: 25-31 (1994)).
Further, a method which antagonises the production of free arachidonic acid, its metabolites or PAF will have clinical utility in the treatment of a variety of allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria, as well as reperfusion injury and other disease involving lipid mediators of inflammation. Many published patent applications or issued U.S. patents exist which describe various compounds having utility as PAF or eicosanoid antagonists. Such patents include U.S. Pat. Nos. 4,788,205, 4,801,598, 4,981,860, 4,992,455, 4,983,592, 5,011,847, 5,019,581 and 5,002,941.
Accordingly, as CoA-IT is involved in arachidonic acid and phospholipid metabolism, inhibition of such an enzyme would be useful for the treatment of inflammatory, allergic and hypersecretory conditions or disease states caused thereby. Therefore, a method by which CoA-IT is inhibited will consequently and preferentially decrease the arachidonate content of 1-alkyl- and 1-alkenyl-linked phospholipids and will therefore decrease the production of pro-inflammatory mediators such as free arachidonic acid, prostaglandins, leukotriene and PAF during an inflammatory response.
There remains a need for treatment, in this field, for compounds which are CoA-IT inhibitors, i.e. compounds which are capable of inhibiting, or interfering with this enzyme and thereby decrease production of the pro-inflammatory mediators.